Polymorphisms are associated with a number of enzymes involved in the metabolic activation or detoxification of tobacco carcinogens. By use of case-control molecular epidemiology studies, the association between genetic or phenotypic polymorphisms and cancer susceptibility has been investigated. The most well-defined correlation for susceptibility to tobacco-induced cancers is the null GSTM1 genotype and lung cancer. Some evidence also exists demonstrating a link between CYP1A1 polymorphisms and cancer susceptibility. As xenobiotic-metabolizing enzymes play an integral role in the activation and detoxification of many potent tobacco carcinogens such as polycyclic aromatic hydrocarbons (PAHs) like benxo(a)pyrene, and tobacco-specific nitrosamines (TSNAs) such as 4-(methyl-nitrosamino)-1-(3-pyridyl)-butanone (NNK), the applicant further hypothesizes that susceptibility to either PAH- or TSNA-induced oral cavity carcinogenicity will be reflected in the genotypes of these enzymes. Extensive epidemiological data have established that tobacco use is the major risk factor for squamous cell carcinoma of the oral cavity (OCSCC), with greater than 85% of oral cancer linked to the use of tobacco. Studies reporting on xenobiotic-metabolizing enzyme polymorphisms as markers for individual susceptibility to tobacco-induced OCSCC have not yet been performed. The applicant hypothesizes that polymorphic markers of xenobiotic-metabolizing enzymes can be used to assess individual susceptibility to OCSCC. In this application, studies are proposed to examine genetic polymorphic markers of xenobiotic-metabolizing enzymes involved in tobacco carcinogen metabolism in a case-control study of oral cavity cancer cases versus frequency-matched non-cancer controls at Memorial Sloan-Kettering Cancer Center, Temple University Hospital, and the New York Eye and Ear Infirmary, in order to assess individual susceptibility to OCSCC. The multi-institutional nature of this proposal will enable assessment of individual susceptibility to OCSCC in different racial groups (i.e. Caucasian versus African American) within the American population. The major goal of this application will be to elucidate highly susceptible genotypic profiles for OCSCC. In addition, studies will be done to elucidate new polymorphic markers of OCSCC risk, focusing on the CYP1A2 enzyme, which is a strong metabolizer of the potent tobacco specific nitrosamine, NNK. A third major aim will be to compare the polymorphism profile of xenobiotic-metabolizing enzymes from oral cancer patients with the p53 mutational profile of a subset of OCSCCs obtained from the same patients. These studies should enable accumulation of important data concerning the contribution of specific carcinogen groups to the carcinogenicity of tobacco and tobacco smoke.